Emerging evidence for compromised axonal bioenergetics and axoglial metabolic coupling as drivers of neurodegeneration.

Impaired bioenergetic capacity of the nervous system is thought to contribute to the pathogenesis of many neurodegenerative diseases (NDD). Since neuronal synapses are believed to be the major energy consumers in the nervous system, synaptic derangements resulting from energy deficits have been suggested to play a central role for the development of many of these disorders. However, long axons constitute the largest compartment of the neuronal network, require large amounts of energy, are metabolically and structurally highly vulnerable, and undergo early injurious stresses in many NDD. These stresses likely impose additional energy demands for continuous adaptations and repair processes, and may eventually overwhelm axonal maintenance mechanisms. Indeed, pathological axon degeneration (pAxD) is now recognized as an etiological focus in a wide array of NDD associated with bioenergetic abnormalities. In this paper I first discuss the recognition that a simple experimental model for pAxD is regulated by an auto-destruction program that exhausts distressed axons energetically. Provision of the energy substrate pyruvate robustly counteracts this axonal breakdown. Importantly, energy decline in axons is not only a consequence but also an initiator of this program. This opens the intriguing possibility that axon dysfunction and pAxD can be suppressed by preemptively energizing distressed axons. Second, I focus on the emerging concept that axons communicate energetically with their flanking glia. This axoglial metabolic coupling can help offset the axonal energy decline that activates the pAxD program but also jeopardize axon integrity as a result of perturbed glial metabolism. Third, I present compelling evidence that abnormal axonal energetics and compromised axoglial metabolic coupling accompany the activation of the pAxD auto-destruction pathway in models of glaucoma, a widespread neurodegenerative condition with pathogenic overlap to other common NDD. In conclusion, I propose a novel conceptual framework suggesting that therapeutic interventions focused on bioenergetic support of the nervous system should also address axons and their metabolic interactions with glia.